tbuckley/cabot-search huggingface dataset:
PATH-41. INTEGRATED MOLECULAR ANALYSIS REVEALS HYPERMETHYLATION AND OVEREXPRESSION OF HOX GENES TO BE POOR PROGNOSTICATORS IN IDH MUTANT GLIOMA
Authors: Yasin Mamatjan, Mathew Voisin, Farshad Nassiri, Severa Bunda, Andreas von Deimling, Kenneth Aldape, Gelareh Zadeh
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Diffuse gliomas represent over 80% of malignant brain tumors ranging from low-grade to aggressive high-grade lesions. Within IDH-mutant gliomas there is a high variability in survival and a need to more accurately predict outcome. METHODS To identify and characterize a predictive signature of outcome in gliomas, we utilized an integrative molecular analysis (using methylation, mRNA, copy number variation (CNV) and mutation data), analyzing a total of 729 IDH-mutant samples including a test set of 99 from University Health Network (UHN) and two validation cohorts including the German Cancer Research Center (DKFZ) and The Cancer Genome Atlas (TCGA). RESULTS Cox regression analysis of methylation data from the UHN cohort identified CpG-based signatures that split the glioma cohort into two prognostic groups strongly predicting survival that were validated using two independent cohorts from TCGA and DKFZ (all p-values&amp;lt; 0.0001). The methylation signatures that predicted poor outcome also exhibited high CNV instability and hypermethylation of HOX gene probes. Integrated multi-platform analyses using mRNA and methylation (iRM) showed that parallel HOX gene overexpression and simultaneous hypermethylation were significantly associated with increased mutational load, high aneuploidy and worse survival (p-value&amp;lt; 0.0001). A 7-HOX gene signature was developed and validated using the most significantly associated HOX genes with patient outcome in both 1p/19q codeleted and non-codeleted IDHmut gliomas. CONCLUSIONS HOX gene methylation and expression provide important prognostic information in IDH-mutant gliomas that are not captured by current molecular diagnostics. A 7-HOX gene signature of outcome shows significant survival differences in both 1p/19q codeleted and non-codeleted IDH-mutant gliomas.
NCOG-19. SEX DIFFERENCES IN GLIOBLASTOMA TREATMENT AND ADVERSE EVENTS
Authors: Mantas Dmukauskas, Gino Cioffi, Corey Neff, Mackenzie Price, Kristin Waite, Carol Kruchko, Quinn Ostrom, Jill Barnholtz-Sloan
Journal: Neuro-Oncology (2023)

Abstract Despite aggressive therapies, the survival rates for gliomas remain complex and accumulating evidence indicates that there are sex differences in patient response to treatment and the development of adverse events (AE). We utilized the Surveillance, Epidemiology and End. RESULTS: Program (SEER)-Medicare dataset to examine sex differences in treatment patterns and AEs in patients 65 years and older diagnosed with glioblastoma. We identified 15,693 individuals (≥65 years) diagnosed with glioblastoma between 2004-2017. Sex differences were assessed based upon their treatment modality: no-treatment (NT), standard treatment (ST) (surgery + radiation + chemotherapy), or other treatment (OT) (any other combination of surgery, radiation and/or chemotherapy). Multivariable models were used to determine the odds of males versus females experiencing an AE by treatment group. Sex differences in survival were assessed using Kaplan-Meier and Cox proportional hazards models. There was a significant sex difference in the type of treatment received by glioblastoma patients, with males receiving more ST than females (38% v 34%; p&amp;lt; 0.001). Females treated with ST had increased odds of rheumatoid arthritis or collagen vascular disease (OR=0.42; 95%CI, 0.30-0.59; p&amp;lt; 0.001). Females receiving OT had an increased odds of rheumatoid arthritis or collagen vascular disease (OR=0.59; 95%CI, 0.44-0.78; p&amp;lt; 0.001), and mood disorders (OR=0.81; 95%CI, 0.72-0.90; p&amp;lt; 0.001). Males receiving NT had an increased odds of blood disorders (OR=1.48; 95% CI, 1.12-1.96; p=0.006), cardiac events when treated with ST (OR=1.24; 95%CI, 1.10-1.41; p&amp;lt; 0.001), and respiratory events when treated with OT (OR=1.20; 95%CI, 1.07-1.35; p=0.002). Females with glioblastoma, receiving ST had an increased adjusted overall survival compared to males (p&amp;lt; 0.001), whereas no sex difference were observed in those receiving OT or NT. Our analysis demonstrates that there are sex differences in odds of AE and overall survival associated glioblastoma treatment, which could impact clinical treatment decisions.
CNSC-41. DOES ISCHEMIC STROKE DRIVE BRAIN TUMOR PROGRESSION?
Authors: Qi Ye, Christine Madamba, Latha Khatri, Yuhui Yang, Ganesh Rao, Hyun Kyoung Lee
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma multiforme is the most common and lethal primary brain tumor, with a 5-year survival rate of less than 5%. Its complex pathophysiology, highlighted by massive inflammatory responses, enhances tumor progression and impedes therapeutic interventions, leading to its dismal prognosis. Inflammatory responses are also a cardinal feature of brain injury and remarkably, clinical evidence from large-scale patient cohort studies indicates a link between glioma and cerebral ischemic stroke, where approximately 10% of ischemic stroke patients develop glioma. This observation suggests that brain injury may be a risk factor for the development of brain tumors; however, whether and how stroke occurrence promotes brain tumor progression is unknown. To address this knowledge gap, we employed a photothrombotic stroke mouse model in conjunction with established glioma models. In these models, we observed a significant increase in tumor cell proliferation and infiltration towards the infarct region and blood-brain barrier disruption. Intriguingly, spatial transcriptomic analysis in stroke-glioma models highlighted altered pH regulation in the microenvironment at the leading edge of tumor cells near stroke lesions. Further analysis revealed that the astrocytic pH regulator, Slc4a4, is significantly downregulated in the infiltrating tumor cells near infarct lesions, and that Slc4a4 inhibits tumor progression in our glioma models. Based on patient cohort studies that link glioma occurrence with cerebral ischemia and our new mouse model results, our data demonstrates that exposure to cortical ischemia-induced-hypoxia during tumorigenesis, promotes malignant glioma progression by altering the brain microenvironment via pH modulation. These conceptually innovative studies will integrate our new stroke-glioma models and advanced methodologies to investigate the stroke-glioma interaction via hypoxia and pH modulation, potentially identifying new therapy targets.
TMIC-33. UNDERSTAND AND TARGET ASTROCYTE REACTIVITY IN BRAIN TUMORS TO PREVENT RADIORESISTANCE
Authors: Pauline Jeannot, Tracy Berg, John Dawson, Richard Eliott, Neil Carragher, Alexander Pietras
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma multiforme (GBM) is the most aggressive type of glioma and deadliest brain tumor. Despite aggressive treatments including surgery, chemo-, and radiotherapy, tumors invariably recur as incurable lesions, and the median survival is approximately 15 months after diagnosis. Recurrence is tightly linked to tumor cell resistance to ionizing radiation (IR), a feature that in turn is linked to stem cell characteristics of tumor cells. Previous results from our lab indicate that stromal astrocytes respond to IR with a reactive phenotype that in turn promotes therapeutic resistance of neighboring tumor cells. Our objectives were to i) identify pathways involved in IR-induced astrocyte reactivity; ii) identify compounds able to inhibit IR-induced astrocyte reactivity. We used two complementary approaches to meet our objectives. Using an antibody array we found that JNK and ABL pathways were activated following IR in primary human astrocytes. To validate their involvement in the induction of astrocyte reactive phenotype we used an image-based readout combining the changes in the expression of reactivity markers and in the morphology of astrocytes. For the second approach, we used a similar readout to perform an image-based drug screen which aimed to identify compounds able to inhibit IR-induced astrocyte reactivity. The drug libraries used consisted of approved drugs to get candidates with potential for drug repurposing. We identified 20 compounds inhibiting IR-induced astrocyte reactivity and amongst them, 10 are brain-penetrant compounds that could make them good candidates for repurposing in GBM. An in vivo test is now ongoing with 2 of these compounds in a PDGFA/PDGFB-driven mouse model of GBM to validate their efficiency to increase radiosensitivity of the tumor cell by inhibiting astrocyte reactivity
RADT-26. IMPROVING RADIATION TARGET VOLUME DEFINITION FOR GLIOBLASTOMA USING PREDICTIONS OF TUMOR RECURRENCE FROM MACHINE LEARNING AND PRE-RADIOTHERAPY ADVANCED MRI
Authors: Nate Tran, Tracy Luks, Jacob Ellison, Devika Nair, Yan Li, Angela Jakary, Bo Liu, Oluwaseun Adegbite, Javier Villanueva-Meyer, Nicholas Butowski, Jennifer Clarke, Susan Chang, Steve Braunstein, Hui Lin, Olivier Morin, Janine Lupo
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Standard-of-care (SOC) radiation therapy (RT) planning only utilizes a fairly 1.5-2cm uniform expansion of T2-weighted-FLAIR MRI lesion to generate a clinical target volume (2cm-CTV), without considering the spatial heterogeneity and infiltrative nature of glioblastomas. This study aimed to use multi-parametric MRI with 2 artificial intelligence (AI)-based approaches to predict regions of subsequent tumor progression and compare the resulting predictions to the 2cm-CTV, with the hypothesis that applying deep learning will lead to improved detection of subclinical disease that is under-treated, and more accurately delineate areas at higher risk for progression, than the uniform 2cm-CTV. METHODS We used normalized maps of anatomical, diffusion, and metabolic MRI post-surgical resection and before RT and chemotherapy from 72 patients newly-diagnosed with glioblastoma to train Random-Forest and deep-learning UNet models to identify voxels that later exhibit progression by either the contrast-enhancing-lesion (CEL) or T2-lesion (T2L). All models were trained/validated on 54 and tested on 18 patients after careful inter-exam alignment and normalization. Model performance was compared to the 2cm-CTV using a Progression-Coverage-Coefficient (PCC), a weighted Dice coefficient that accounts for tumor-size. RESULTS Random-Forest models were able to predict subsequent contrast-enhancing (CE) and T2 non-enhancing (NE) progression with an average respective test AUC of 0.88 and 0.82, with 15.6%/9.6% higher performance on patients who progressed early. The 2cm-CTV treatment plan achieved the highest sensitivity (0.833 vs 0.795) but also the lowest specificity (0.879 vs 0.935), over-treating normal-appearing-brain. Our deep learning model outperformed the 2cm-CTV in covering the progressed lesion, with the highest specificity (0.935 vs 0.879), PCC (0.741 vs 0.734), and had comparable sensitivity (0.795) to the 2cm-CTV, while sparing more normal brain compared to the 2cm-CTV. CONCLUSION This study demonstrates the potential benefit of using multi-parametric MRI with deep learning to assist in RT treatment planning to reduce excessive treatment of normal brain parenchyma.
TMIC-05. UNVEILING THE IMPACT OF PTN-PTPRZ1 SIGNALING ON GLIOBLASTOMA PROGRESSION THROUGH TUMOR MICROENVIRONMENT COMMUNICATION
Authors: Weihong Ge, Ryan Kan, Elisa Fazzari, Daria Azizad, Joyce Ito, Can Yilgor, Christopher Tse, Andrew Tum, Kunal Patel, David Nathanson, Aparna Bhaduri
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most lethal primary brain tumor with high rate of recurrence. GBM’s high inter- and intra-heterogeneity present a huge challenge to both disease modeling and treatment. Recent progress in the field has highlighted the role of signals associated with the microenvironment factor in driving tumor progression, suggesting that more detailed characterizations of the GBM microenvironment may provide novel therapeutic targets. In this study, we used a novel stem cell derived cortical organoid transplantation model, where we transplanted patient IDH wild type GBM cells onto organoids and provided multiple culture conditions to explore the impact of the environment on tumor cell identity. After several weeks of culture, single cell RNA-sequencing of tumor and non-neoplastic organoid cells was used to profile molecular features, demonstrating not only cellular composition of GBM and its surrounding normal brain cell, but also the bidirectional communication between the two. We observed functional heterogeneity where individual tumors responded differently to environmental perturbations. However, the most significant cell-cell interaction between tumors and the microenvironment was found to be PTN-PTPRZ1, which is well-maintained across all transplantation models we tested, as well as in re-analysis of published patient data that included tumor and normal cells. Encouraged by our previous works as well as others, which have revealed PTPRZ1 as an outer radial glia marker gene driving tumor invasion, we further verified PTN/PTPRZ1 expression not only in our organoid transplantation models but also on FFPE sections from GBM patients and mouse xenograft samples. These data suggest that this signaling axis promotes tumor progression through tumor – microenvironmental crosstalk, and using the organoid model we show a functional role for this communication. Together, this study presents a GBM organoid transplantation modeling system, which we leverage to detect a promising therapeutically target existing between GBM and its microenvironment.
TMIC-55. TURNING ENEMY INTO ALLY: HIJACK BRAIN TUMOR CELLS TO BREAK DOWN THE BLOOD-TUMOR BARRIER
Authors: Shahrzad Bahrampour, Xi Huang
Journal: Neuro-Oncology (2023)

Abstract A major obstacle in brain cancer treatment is the blood-tumor barrier (BTB), which limits the delivery of a vast majority of therapeutic agents. Medulloblastoma (MB), the most common pediatric malignant brain tumor, consists of four subgroups (WNT, SHH, Group 3, Group 4). Increasing BTB permeability of non-WNT MB is essential for effectively treating patients by overcoming this drug delivery impediment. Since the BTB is exposed to biofluids such as blood and brain interstitial fluid, which present dynamic osmotic challenges, we hypothesized that cell volume regulation plays a crucial role in BTB integrity. Using a genetically engineered mouse model of SHH MB, we show that tumor-specific knockout of volume-regulated ion channel, Lrrc8a, significantly increases BTB permeability and enhances the therapeutic response of MB-bearing mice to vismodegib, an FDA-approved antagonist of the SHH pathway. Lrrc8a-deficient tumor cells develop ectopic contact with blood vessels, permitting tumor cell-derived Tgfβ2 to activate Tgfβ signaling in endothelial cells. Consequently, endothelial cells in Lrrc8a knockout MB lose endothelial characteristics and gain mesenchymal features, indicative of Tgfβ signaling-induced endothelial-mesenchymal transition (EndMT). Furthermore, tumor-specific LRRC8A knockdown enhances BTB permeability in a xenograft human Group 3 MB model. Collectively, our findings establish Lrrc8a/LRRC8A as a therapeutic target to increase the therapy response of MB and provide evidence that inducing EndMT could be a strategy for enhancing BTB permeability to treat brain cancer.
TMIC-52. HISTONE H3K27ME3 LEVEL GOVERN TUMOR-ASSOCIATED MICROGLIA REPROGRAMMING IN RESPONSE TO GBM
Authors: Sangjo Kang, Anirudh Sattiraju, Mary Ughetta, Alexander Tsankov, Roland Friedel, Hongyan Zou
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GBM) is the most common malignant primary brain tumor and its invasive nature makes complete dissection difficult. However, how GBM invade in the brain is poorly understood. Although, microglia are the resident immune cells in the brain that can support GBM invasion, their roles are yet elusive. Here, we retraced early steps of GBM invasion and their interaction with tumor-associated microglia (TAM) in a highly infiltrative murine GBM model in immunocompetent background. We show that microglia are activated in a wide tumor field ahead of GBM invasion, followed by glial net formation, encircling invading tumors. Next, physical contacts with GBM cells initiate an astounding morphological, and functional transformation of microglia and marrow-derived macrophages to form collectively organized migration streams with intertwined GBM cells. Here we show that Kdm6b, a H3K27me3 demethylase, is induced in TAMs during this process. Intriguingly, GBM disseminated more widely in juvenile host brains, which was associated with highly induced Kdm6b expression. Moreover, we show that Kdm6b inhibition with small chemical inhibitor GSKJ-4, perturbs TAM reprogramming, and GBM invasion. Together, our data reveal that microglia reprogramming provide directional cues for GBM invasion through epigenetic mechanisms and this may give insights to halt GBM invasion.
PATH-16. SURVIVAL ANALYSIS OF ADULT MIDLINE-LOCATED GLIOMAS: DOES THE H3K27 ALTERATION IN ADULT MIDLINE-LOCATED GLIOMAS ACTUALLY INDICATE A POOR PROGNOSIS?
Authors: Jong Hee Chang, In-Ho Jung, Jihwan Yoo, Hun Ho Park, Jaejoon Lim, Ju Hyung Moon, Eui-Hyun Kim, Seok-Gu Kang, Hong In Yoon, Se Hoon Kim
Journal: Neuro-Oncology (2023)

Abstract OBJECTIVE Although pediatric midline-located gliomas (MGs) with H3K27 alteration have been widely known to have a poor prognosis, few researchers have assessed adult MGs with H3K27 alteration. We aimed to determine the effect of H3K27 alteration on the prognosis of adult MGs. And we tried to identify the factors affecting the prognosis of diffuse midline glioma (DMG). This is the first study to investigate the prognosis of adult DMGs according to histological grade and is the largest study to investigate the survival of adult patients with DMGs. METHODS We reviewed the charts of adult patients diagnosed with MG after undergoing resection or biopsy at our institution between 2010 and 2020. The Gehan–Breslow–Wilcoxon test was used for univariate survival analysis, and the Cox regression proportional hazard model was used for multivariate survival analysis. RESULTS Among the 125 adult MGs identified, 45 (36.0%) showed H3K27 alterations. Surprisingly, the H3K27 alteration group showed significantly better median survival than the wildtype group in patients of all ages (23.1 vs. 15.9 months, p=0.040). However, after adjusting for age, the difference in survival between the H3K27-alteration and wildtype groups was not significant (p=0.121). In the survival analysis of 45 patients with DMG, low histological grade, KPS ≥ 80, total resection, and concurrent chemoradiation therapy were associated with significantly better survival. CONCLUSION Adult MGs did not show a poor prognosis due to H3K27 alterations, unlike pediatric cases. The prognosis of adult DMGs is based on the histological grade, KPS, adjuvant treatment, and extent of tumor resection.
NIMG-47. LONGITUDINAL TRAJECTORIES FROM SERIAL SURVEILLANCE MRI IMAGING OF PROGRESSIVE IDH MUTANT LOW-GRADE GLIOMA PATIENTS
Authors: Kaleigh Fetcko-Fayad, Xiaojun Zheng, Devon Godfrey, Henry Kirveslahti, Sayan Mukherjee, Kyle Lafata, Jennifer Thomas, Katherine Peters, Marc Ryser
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Most patients with isocitrate dehydrogenase mutant (IDHm) low-grade glioma (LGG) undergo active MRI surveillance after initial surgery. Timely biopsy referral during surveillance is a complex trade-off between avoiding the harms of unnecessary surgery and early detection of transformation. Serial surveillance MRIs could be leveraged to develop dynamic imaging markers, yet prior research has primarily focused on the prognostication of pre-treatment images. We piloted the feasibility of an automated pipeline using patient-specific imaging trajectories. METHODS We retrospectively identified 12 progressive IDHm LGG patients and collected serial surveillance MRIs. A previously developed segmentation model was fine-tuned on a subset of T2/FLAIR images (n=49) before automated tumor segmentation was performed on all MRIs. We extracted geometric and topological tumor features, including volume, cross product, and Euler Characteristic Transform, from each MRI. We used piecewise linear regression to quantify feature trajectories and identify change points in feature growth rates. RESULTS Twelve patients received 14 biopsies/repeat resections (10 with transformation, 4 without) and 282 MRIs (median per patient: 17, range: 10-40). All biopsies/repeat resections were preceded by a change point in tumor volume trajectory, indicating an increase in tumor growth rate preceding clinician-determined MRI progression and biopsy referral. The mean increase in volume growth rate, pre to post change point, was 2.3cm3/month (SE: 0.9) in biopsies/repeat resections with transformation, compared to 1.1cm3/month (SE: 0.6) in biopsies/repeat resections without transformation. Among the ten patients with transformation, the median time from IDHm LGG diagnosis to transformation was 64.8 months (range: 38.6-141.1), and the median time between volume change point and transformation was 15.6 months (range: 4.6-28.2). DISCUSSION This pilot study suggests that feature trajectories from serial MRIs of IDHm LGG patients may advance the detection and treatment of transformed lesions by 12-18 months. Larger studies can corroborate these findings and inform clinical decision-making.
PATH-40. “DE NOVO REPLICATION REPAIR DEFICIENT GLIOBLASTOMA, IDH-WILDTYPE” IS A DISTINCT GLIOBLASTOMA SUBTYPE IN ADULTS THAT MAY BENEFIT FROM IMMUNE CHECKPOINT BLOCKADE
Authors: Sara Hadad, Nancy Ann Oberheim Bush, Jennifer Clarke, Jennie Taylor, Jacob Young, Javier Villanueva-Meyer, Yalan Zhang, Rohit Gupta, Jasper Wu, Ajay Ravindranathan, Shawn Hervey-Jumper, Susan Chang, Mitchel Berger, Annette Molinaro, David Solomon
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma is clinically and molecularly heterogeneous, and new predictive biomarkers are needed to identify those patients most likely to respond to specific treatments. Through prospective genomic profiling of 459 primary treatment-naïve IDH-wildtype glioblastomas in adults, we identified a subgroup (2%, 8/459) defined by somatic hypermutation and DNA replication repair deficiency due to mismatch repair gene inactivation and/or proofreading domain mutation in the DNA polymerase POLE. The deleterious mutations in mismatch repair genes were often present in the germline in the heterozygous state with somatic inactivation of the remaining wildtype allele, consistent Lynch syndrome-associated glioblastomas. All tumors were hypermutated ( &amp;gt;20 somatic nonsynonymous mutations/Mb), while the three tumors with POLE mutations were “ultrahypermutated” with &amp;gt;150 mutations/Mb. The median age at diagnosis was 52 years (range 27-78), compared with median age of 63 years for the other 451 patients with conventional glioblastoma. All tumors were diffuse astrocytic gliomas of the giant cell histologic subtype. They lacked EGFR amplification and only rarely had TERT promoter mutation (1/8), CDKN2A homozygous deletion (1/8), or the combination of trisomy 7 and monosomy 10 (1/8). Instead, they harbored frequent inactivating mutations in the TP53, NF1, PTEN, ATRX, and SETD2 genes ( &amp;gt;50% each) and recurrent activating mutations in PDGFRA (4/8). DNA methylation profiling revealed they did not align with known glioblastoma methylation classes, but instead mostly classified as “Diffuse pediatric-type high grade glioma, RTK1 subtype, subclass A (novel)”. Some patients were treated with immune checkpoint blockade (nivolumab or pembrolizumab) and survived over three years. The median overall survival for the cohort was 37.4 months (95% CI: 22-not reached), compared to 15.4 months (95% CI: 14.7-17.9) for the other 451 patients. We speculate that “de novo replication repair deficient glioblastoma, IDH-wildtype” represents a biologically distinct subtype that may benefit from prospective identification and treatment with immune checkpoint blockade.